A process and an arrangement of this type are known from WO 97/42868. This proposes intermittent delivery pulses in order to, on the one hand, enable a continuous signal calibration and, on the other hand, to accelerate the measurement process. In this process the perfusate volume which is at that moment in the microdialysis probe adjusts during the resting phases between the delivery pulses to the concentration of the tissue glucose as a result of the dialysis process whereas adjacent volume regions in the subsequent liquid column that is transported further at a high flow rate remain largely unchanged. A signal peak is observed during a delivery pulse in the measuring cell which corresponds to the concentration gradient and from which the glucose content of the dialysate and thus also of the body fluid can be determined. Perfusion fluid containing glucose, the specified glucose concentration of which defines the baseline value of the signal peak, is used for the calibration. A prerequisite for this is a linear sensor behaviour during the dialysis phases in addition to a complete concentration equilibration and it is assumed that the concentration profile in the volume transported away from the probe does not decay until it reaches the measuring cell. However, especially the latter assumption is frequently not the case since mixing occurs especially when the flow is laminar.
In addition diffusion exchange disturbs the glucose equilibrium in the tissue surrounding the probe.
Taking this as a starting point the object of the invention is to avoid the aforementioned disadvantages and in particular concentration disturbances in the body fluid and to enable an exact glucose determination with a reduced dialysis period.
The feature combinations of determining the glucose concentration in a body fluid, in particular tissue fluid, in which perfusate containing glucose is passed through a microdialysis probe inserted into the body fluid and dialysate obtained in this process is transported to a measuring cell, and in which measurement signals that correlate with the glucose content of the dialysate are measured at the measuring cell, characterized in that the starting content of glucose in the perfusate is adjusted to the glucose content of the body fluid by means of a control device in accordance with a command variable derived from the measurement signals of the measuring cell are proposed to achieve this object.
Advantageous embodiments and further developments of the invention derive from the following:
A method as described above characterized in that when the control deviation is negligible the momentary starting content of the glucose in the perfusate is determined as a measure for the glucose content of the body fluid.
A method as described in either of the preceding paragraphs characterized in that the starting content of glucose in the perfusate is determined from the adjusting variable of an adjuster of the control device.
A method as described in one of the preceding three paragraphs, characterized in that the glucose content of the perfusate is measured before it is passed into the microdialysis probe.
A method as described in one of the preceding four paragraphs, characterized in that the starting content of glucose in the perfusate is influenced by flow mixing two perfusion liquids with different glucose concentrations provided in two separate reservoirs.
A method as described in one of the preceding five paragraphs, characterized in that the perfusate is passed through the microdialysis probe (10) in alternating successive transport and dialysis intervals at different flow rates, the flow rate during the transport intervals being higher than during the dialysis intervals.
A method as described in the preceding paragraph, characterized in that the flow rate during the transport intervals is increased to such an extent that the starting content of glucose in the perfusate during passage through the microdialysis probe remains essentially constant and that during the dialysis intervals the transport is interrupted or at least the flow rate is reduced to such an extent that the glucose concentration of the dialysate approximates the glucose content of the body fluid.
A method as described in one of the preceding seven paragraphs, characterized in that the command variable is determined by integration or differentiation of the time course of the measurement signals.
A method as described in one of the preceding three paragraphs, characterized in that the command variable is determined by qualitative detection of signal peaks in the time course of the measurement signals.
A method as described in one of the preceding four paragraphs, characterized in that the command variable is determined by comparing the actual signal curve of the measurement signals with calibrated signal patterns deposited in a storage medium.
A method as described in one of the preceding five paragraphs, characterized in that the command variable is determined from the peak value of the signal time course of the measurement signals during each transport interval.
A method as described in one of the preceding six paragraphs, characterized in that the command variable can be determined according to the glucose content c of the body fluid according to the relationship
  c  =                    [                                            S              g                                                                        S                  g                                ·                                  (                                      1                    -                    b                                    )                                            +                              b                ·                                  S                  0                                                              -          1                ]            ·      a      ·              c        0              +          c      0      in which Sg denotes the peak value and S0 denotes the base line value of the signals measured during a transport interval and c0 is the momentary starting content of glucose in the perfusate and a, b are empirically determined correction factors compensating for diffusion and mixing and remaining recovery effects during the transport interval.
A method as described in one of the preceding twelve paragraphs, characterized in that the starting content of glucose in the perfusate is regulated discontinuously by a two-point control process in which the starting content of glucose in the perfusate is changed by a predetermined adjustment value when there is a control deviation.
In addition, the feature combinations of the arrangement for determining the glucose concentration in a body fluid, in particular tissue fluid, comprising a microdialysis probe for the diffusion exchange of glucose with surrounding body fluid, a perfusion device for perfusing the microdialysis probe with glucose-containing perfusate to obtain dialysate and a measuring cell located after the microdialysis probe for detecting measurement signals that correlate with the glucose content of the dialysate, characterized by a control device which adjusts the starting content of glucose in the perfusate to the glucose content of the body fluid in accordance with a command variable derived from the measurement signals of the measuring cell are proposed to achieve this object.
Advantageous embodiments and further developments of the invention derive from the following:
The arrangement as described in the preceding paragraph, characterized by an evaluation unit to determine the momentary starting content of glucose in the perfusate when the control deviation is negligible as a measure for the glucose content of the body fluid.
The arrangement as described in the preceding two paragraphs, characterized in that the perfusion device has a perfusate store and a transport unit for the preferably intermittent transport of perfusate.
The arrangement as described in the preceding paragraph, characterized in that the perfusate store has at least two separate reservoirs to hold perfusion liquids with different glucose concentrations.
The arrangement as described in the preceding two paragraphs, characterized in that the perfusate store has a first reservoir containing a glucose-free perfusion liquid and a second reservoir containing a glucose-containing perfusion liquid.
The arrangement as described in one of the preceding five paragraphs, characterized in that the control device has a flow mixer preferably comprising a mixing valve or clock-pulsed directional control valve as an adjuster to adjust the starting content of glucose in the perfusate.
The arrangement as described in the preceding paragraph, characterized in that the inlet side of the flow mixer is connected to at least two reservoirs for feeding in perfusion fluids with different glucose contents and the outlet side of the flow mixer connects a perfusate tube leading to the microdialysis probe.
The arrangement as described in one of the preceding seven paragraphs, characterized in that the control device has a digitally operated controller preferably in the form of a microcontroller.
Further, the feature combinations of arrangement for determining the glucose concentration in a body fluid, in particular tissue fluid, comprising a microdialysis probe inserted into the body fluid, at least two reservoirs for holding perfusion liquids with different glucose contents, a transport unit to perfuse the microdialysis probe with glucose-containing perfusate to obtain dialysate and a flow-through measuring cell located downstream of the microdialysis probe to register measurement signals that correlate with the glucose content of the dialysate, characterized by a control device connected on the input side to the measuring cell which control device has a flow mixer connected on the inlet side to the reservoirs and on the outlet side to the microdialysis probe which acts as an adjuster to regulate the starting content of glucose in the perfusate are proposed to achieve this object.
The idea behind the invention is to adapt the glucose content of the perfusate in a self-adjusting and adaptive manner to the glucose concentration of the body fluid. Accordingly the method proposed to achieve the above-mentioned object is to adapt the initial content of the glucose in the perfusate to the glucose content of the body fluid by means of a control unit according to a command variable derived from the measurement signals of the measuring cell. This offsets glucose gradients and hence reduces the period required for a complete dialysis equilibration. It also avoids interfering effects due to glucose gradients even with a high flow rate through the microdialysis probe and glucose variations in the body fluid.
A particularly preferred embodiment of the invention envisages determination of the momentary starting content of glucose in the perfusate as a measure for the glucose content of the body fluid when the deviation is negligible. This enables a quantitative indirect determination of the concentration by means of the momentary actual value of the regulating variable while the continuously measured signals from the measuring cell are only used as regulating input variables. Alternatively additionally, it is in principle possible to derive the glucose content of the body fluid directly from the measurement signals.
The initial content of glucose in the perfusate is advantageously determined from the adjustable variable of the adjuster of the controlling device. This measure enables the initial content to be determined accurately for example by comparison with normalized values in tables without requiring additional glucose sensors. However, in principle it is also possible to measure the glucose content of the perfusate before it is passed into the microdialysis probe.
For a variable adjustment it is advantageous when the initial content of glucose in the perfusate is influenced by flow mixing two perfusion fluids with different glucose concentrations that are kept ready in two separate reservoirs.
In a particularly preferred embodiment of the invention the perfusate is passed through the microdialysis probe in alternating consecutive transport and dialysis intervals at different flow rates, the flow rate during the transport intervals being higher than during the dialysis intervals. As a result the measurement can be shortened as a whole and the evaluation can be further simplified since an existing concentration gradient can be qualitatively detected by means of the measurement signal even if there is only a partial dialysis equilibration. The flow rate should be increased during the transport intervals to such an extent that the starting content of the glucose in the perfusate is essentially maintained as it passes through the microdialysis probe. In contrast the transport is interrupted or at least the flow rate is reduced during the dialysis intervals to such an extent that the glucose concentration in the dialysate approximates the glucose content of the body fluid.
In a particularly simple control process the command variable which defines the target value is determined by integration or differentiation of the time course of the measurement signals or by a qualitative detection of signal peaks in the time course of the measurement signals. Alternatively the command variable can be determined by comparing the actual signal time course of the measurement signals with calibrated signal patterns deposited in a storage medium. An additional method is to determine the command variable from the peak value of the signal time course of the measurement signals during each transport interval. In order to quantitatively define the regulating input signal, the command variable can be determined according to the glucose content c of the body fluid using the relationship
  c  =                    [                                            S              g                                                                        S                  g                                ·                                  (                                      1                    -                    b                                    )                                            +                              b                ·                                  S                  0                                                              -          1                ]            ·      a      ·              c        0              +          c      0      in which Sg denotes the peak value and S0 denotes the base line value of the signals measured during a transport interval and c0 is the momentary starting content of glucose in the perfusate and a, b are empirically determined correction factors compensating for diffusion and mixing and remaining recovery effects during the transport interval.
A particularly simple control function envisages that the initial content of glucose in the perfusate is adjusted discontinuously by a two-point control process in which the starting content of the glucose in the perfusate is changed by a predetermined adjusting value when there is a deviation.
With regard to a measuring arrangement, a control device is proposed to achieve the above-mentioned object which adapts the starting content of the glucose in the perfusate to the glucose content of the body fluid on the basis of a command variable derived from the measurement signals of the measuring cell. An evaluation unit is provided in a preferred embodiment which determines the glucose content of the body fluid corresponding to the momentary starting content of glucose in the perfusate when the deviation is negligible.
The perfusion device contains a store of perfusate and a transport unit to transport perfusate. The transport unit preferably operates at intervals i.e. at different delivery rates in successive time intervals. In order to vary the initial glucose content it is advantageous if the perfusate store has at least two separate reservoirs to hold perfusion liquids with different glucose concentrations. Advantageously the perfusate store has a first reservoir containing a glucose-free perfusion liquid and a second reservoir containing a glucose-containing perfusion liquid. In this case the glucose content in the latter should be above the physiological thresholds. A controller for adjusting the starting content of the glucose in the perfusate which is simple to construct is preferably provided by a flow mixer composed of a mixing valve or a clock-pulsed directional control valve as the adjuster. In this case it is advantageous for the flow mixer to be connected on the inlet side with at least two reservoirs to supply perfusion fluids with different glucose contents and to discharge into a perfusate tube leading to the microdialysis probe.
The control device advantageously has a controller that operates digitally preferably by means of a micro-controller in order to process the signal flow in a variable manner.